Validation of a pharmacokinetic model of colon-specific drug delivery and the therapeutic effects of chitosan capsules containing 5-aminosalicylic acid on 2,4,6-trinitrobenzenesulphonic acid-induced colitis in rats.

A pharmacokinetic model of colon-specific drug delivery developed in a previous study has been validated by use of 5-aminosalicylic acid (5-ASA) as a model anti-inflammatory drug. The simulation curves obtained from the pharmacokinetic model were in good agreement with experimental data obtained after oral administration of 5-ASA-containing chitosan capsules. The concentrations of 5-ASA in the large intestinal mucosa after drug administration were higher than after administration of the drug in carmellose suspension. We then attempted colon-specific delivery of an anti-ulcerative colitis drug, in chitosan capsules, to accelerate healing of 2,4,6-trinitrobenzenesulphonic acid sodium salt (TNBS)-induced colitis in rats. To confirm this therapeutic model, salazosulphapyridine (SASP), a commercially available 5-ASA prodrug, was used as positive control. Colonic injury and inflammation were assessed by measuring myeloperoxidase activity and visual assessment (damage score), respectively. Because SASP is effective against TNBS-induced colitis in rats, use of the SASP-sensitive TNBS-induced colitis model validated the therapeutic effects of 5-ASA-containing chitosan capsules, which were significantly better than those of a suspension of the drug in carmellose. These findings suggest that our pharmacokinetic model of colon-specific drug delivery can accurately evaluate this colon-specific delivery system and that 5-ASA-containing chitosan capsules are more effective than other 5-ASA formulations for treatment of TNBS-induced colitis in rats.

Colon-specific delivery of R68070, a new thromboxane synthase inhibitor, using chitosan capsules: therapeutic effects against 2,4,6-trinitrobenzene sulfonic acid-induced ulcerative colitis in rats.

The objective of this study was to estimate the therapeutic effects of R68070, a new thromboxane synthase inhibitor, on 2,4,6-trinitrobenzenesulfonic acid sodium salt (TNBS)-induced ulcerative colitis in rats. We also examined the acceleration of the healing effect of R68070 with chitosan capsules to achieve its colon-specific delivery. The colonic injury and inflammation were assessed by measuring the myeloperoxidase (MPO) activities, colon wet weight/body weight (C/B) ratio and the damage score, respectively. These markers were decreased by the oral administration of R68070 with chitosan capsules and carboxymethyl-cellulose (CMC) suspension. The therapeutic effects of R68070 against ulcerative colitis were observed in both dosage forms in a dose dependent manner. In addition, its therapeutic effects were increased by the use of chitosan capsules, compared with CMC suspension. These results suggest that chitosan capsule might be a very useful dosage form for the colon-specific delivery of R68070 as an anti-inflammatory drug and for the therapy of ulcerative colitis.

Chitosan capsules for colon-specific drug delivery: improvement of insulin absorption from the rat colon.

The objective of this study was to estimate colon-specific insulin delivery with chitosan capsules. In vitro drug release experiments from chitosan capsules containing 5(6)-carboxyfluorescein (CF) were carried out by the Japan Pharmacopoeia (J. P.) rotating basket method with some slight modifications. The intestinal absorption of insulin was evaluated by measuring the plasma insulin levels and its hypoglycemic effects after oral administration of the chitosan capsules containing insulin and additives. Little release of CF from the capsules was observed in liquid 1, an artificial gastric juice (pH 1), or in liquid 2, an artificial intestinal juice (pH 7). However, the release of CF was markedly increased in the presence of rat cecal contents. A marked absorption of insulin and a corresponding decrease in plasma glucose levels was observed following the oral administration of these capsules that contain 20 IU of insulin and sodium glycocholate (PA% = 3.49%), as compared with the capsules containing only lactose or only 20 IU of insulin (PA% = 1.62%). The hypoglycemic effect started from 8 h after the administration of chitosan capsules when the capsules entered the colon, as evaluated by the transit time experiments with chitosan capsules. These findings suggest that chitosan capsules may be useful carriers for the colon-specific delivery of peptides including insulin.